Currently, there are eight approved compounds for the treatment of HIV infections that are in the class known as protease inhibitors. Of all classes of HIV medications, the protease inhibitors are the most complex in terms of pharmacokinetics, drug interactions and dosing changes based on those interactions.

Mechanism of Action

All protease inhibitors work in the same manner. They block the activity of the protease enzyme within human cells or new virus particles. This enzyme is what allows a virus to undergo final maturation for producing new viruses that can go out and infect other cells. When the PIs bind to the enzyme, the new viruses still leave the cell, but they are unable to infect other cells.

General Concepts in the PK of Protease Inhibitors

All current protease inhibitors are administered by mouth. They are all absorbed in the gastrointestinal (GI) tract (stomach and intestines). Metabolism, occurring after absorption, is typically performed by the CYP enzymes found in the liver and some in the intestines as well (mainly CYP3A4) (see ABCs of PK). Sometimes, multiple enzymes may affect the same PI (see Figure 2). The PI, in turn, may also affect how these enzymes function. This is why PIs can affect the metabolism of other protease inhibitors and other drugs for different illnesses. The protease inhibitor that has the strongest effect on these enzymes is Norvir. Most of the time, Norvir will slow down how fast the other protease inhibitors are eliminated (see Figure 1: Boosting Protease Inhibitors). This is called PI boosting. As such, the newer and some older PIs are studied with and without Norvir to see if boosting is optional (Reyataz, Lexiva), recommended (Crixivan, Fortovase) or required (tipranavir [experimental], Invirase, Kaletra). The pharmacokinetics of the available protease inhibitors are summarized in Table 1, with and without Norvir boosting. Currently, the only approved protease inhibitor for which boosting is not recommended is Viracept.

Figure 1: Boosting Protease Inhibitors
These are representative drug concentration-time curves for "boosted" and "unboosted" PI regimen dosing schemes. The "boosted" regimen usually provides for higher Cmin than "unboosted". This generally allows for fewer pills to be given per day compared to "unboosted" regimens. Also, there are error bars around each point plotted on this graph. These error bars reflect potentially how different the levels may be from one person to the next or within the same person. Regimens that are "boosted" generally tend to have less variability compared to "unboosted" (smaller error bars).

There are few drug interactions between PIs and the nucleoside/ nucleotide reverse transcriptase inhibitors.

Fortovase and Invirase (Both Are Referred to as Saquinavir)

It would be best to take Fortovase and Invirase at the same time as the Norvir. This is because saquinavir is broken down both by enzymes in the intestines and the liver. Norvir decreases the activity of these enzymes and allows more drug to enter the blood stream and to stay in the blood longer. If one were to separate these medications, the blood level of Fortovase or Invirase may be too low to allow the medication to do its job, and may increase the risk of developing resistance.

Norvir is not the only protease inhibitor that can affect the other protease inhibitors. Many studies have been done on this topic. These interactions are summarized in Table 2. The protease inhibitors also have effects on the pharmacokinetics of some of the other antiretrovirals. See The Non-Nukes for details of the interactions there.

PIs and Viread

Viread decreases the blood levels of Reyataz. The cause of this is not yet known. When a clinician decides to start a patient on both Viread and Reyataz, the Reyataz must be boosted (see Table 1). Additionally, Reyataz and also the combination product of Kaletra have been shown to increase levels of Viread. The clinical implications of this are not yet known. No dose adjustments are recommended at this time (see The Nukes).

* These doses are supported by clinical trials or experience, but are not FDA approved

  1. All doses assume that the product is being used in combination with at least two other active antiretroviral agents

  2. BID = twice a day

  3. QD = once a day

  4. TID = three times a day

  5. These strengths are typically used to complete doses needed to compensate for various drug interactions requiring dose adjustments

  6. Once daily dosing of Lexiva with Norvir is not recommended in patients who are protease inhibitor experienced

  7. Reyataz with Norvir has not been studied in patients receiving HIV treatment for the first time

Day-to-Day Pharmacokinetics

Food Restrictions

Most protease inhibitors do not require food in order to maintain normal, therapeutic drug levels but, and perhaps as important, it may make them more tolerable. The two exceptions to this rule are Reyataz and Viracept. Reyataz requires an acidic stomach environment to be absorbed, and food stimulates the production of acid. The amount of food that should be eaten is not specified by the manufacturer, and is not likely to be of importance. However, certain amounts of food intake have been shown to increase how much Viracept is absorbed with each dose. A meal of at least 500 calories (20% of calories from fat) should be eaten with each dose of Viracept in order to achieve normal therapeutic levels. Increasing the amount of food to 1,000 calories will increase Viracept levels even further. Crixivan, when not given with Norvir, requires little to no food for optimal absorption but food (a low-fat snack only) may make the pills more tolerable.

Missed Doses

Missing doses of most protease inhibitors has been shown to increase the likelihood of a person's virus changing (resistance developing). This makes it less likely that the protease inhibitor will work against the virus. Occasionally, everyone who takes medications for a long period of time will find that they have missed a dose of their medication. When it comes to taking protease inhibitors, it is best to take the missed dose as soon as possible. If the missed dose is not realized until the next dose is due, it is not recommended to take a double dose. If more than one dose has been missed, it is best to consider those doses missed, and start anew with the next dose that is due. Protease inhibitors should not be taken without the other antiretrovirals that are prescribed, and vice versa. So, if doses of any HIV medication are missed due to the lack of availability of any of the components of the regimen, the entire regimen should be stopped until all components are available. Be sure to speak with your doctor's office or pharmacist as soon as you realize you do not have all of your medicines!

Drug Level Testing

Drug level testing (also called therapeutic drug monitoring, or TDM, also see ABCs of PK) is available to most clinicians. There are recommended trough concentrations for several PIs for patients who do not have drug resistant virus (see Figure 6). However, TDM for PIs is not yet routinely recommended. It might be useful in certain circumstances (see ABCs of PK). In patients who have had many antiretrovirals in the past (treatment experienced), what may ultimately guide targets for drug concentrations is the amount of resistance that the person's virus has. Unfortunately, the resistance test that shows the amount of drug needed to decrease the growth of the virus (a phenotype) has many limitations of its own. These limits, in turn, limit the usefulness of TDM for protease inhibitors. Currently, TDM is best done using trough levels (Cmin).

Special Circumstances

There are two of the protease inhibitors to which special discussion should be given. Amprenavir is the active drug that makes up both Lexiva and Agenerase. Lexiva, which was approved in October 2003, is a "prodrug" of Agenerase. A special chemical group was added to the Agenerase molecule. This molecule allows it to be made into a tablet formulation that is more compact, as well as allowing for better absorption from the GI tract. Once Lexiva is absorbed, the extra chemical group is removed in the blood, releasing the active drug, amprenavir. As such, once the drug is absorbed, it has the same pharmacokinetics as amprenavir. The pro-drug formula greatly reduces the number of pills taken.

The second product is saquinavir. It is available under two brand names, manufactured by the same pharmaceutical company. Invirase, which resembles a typical capsule formulation containing a powder, was first approved in late 1995 (in fact, it was the first protease inhibitor approved in the U.S.). This formulation is referred to as a hard-gel capsule. Though Invirase was effective at killing the virus, very little of it was actually absorbed into the blood stream. To improve this aspect, Fortovase was developed. Fortovase offers significantly improved absorption compared to Invirase, and quickly became the preferred formulation. When Fortovase and Invirase are boosted by Norvir, the blood levels of saquinavir are similar. As such, Invirase and Fortovase come close to being equal over the past few years with perhaps greater tolerability of the boosted Invirase compared to boosted Fortovase.

Jim Scott, Pharm.D., is an Assistant Professor of Pharmacy Practice at the Western University of Health Sciences, and Director of the Adherence Improvement Program at the Jeffrey Goodman Special Care Clinic, in Los Angeles, CA. He has been working with HIV patients for over 10 years.

Back to Winter 2005 contents page.

Got a comment on this article? Write to us at